Abstract
The members of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins that are essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of their four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis and tumorigenesis. Here, the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov) is presented, which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 domain lacks the typical π-stacked ladder of charged and aromatic residues on one side of the domain that is seen in other TSP1 domains. Using conservation analysis among orthologous domains, it is shown that a charged cluster in the centre of the domain is the most conserved site and this cluster is predicted to be a potential functional epitope for heparan sulfate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and to derive improved Pfam sequence profiles for the identification of novel TSP1 domains in more than 10 000 proteins across diverse phyla.
Highlights
The CCN proteins are a family of intriguing matricellular proteins, playing regulatory roles in various cellular signalling processes and a range of critical biological functions
By solving the first structure of a thrombospondin module 1 (TSP1) domain in the CCN family, we provide the first insights into the possible molecular functions of the CCN proteins
The structure of CCN3 TSP1 domain was determined by Multi-wavelength anomalous dispersion (MAD) phasing using K2PtCl4 derivative crystals (Table 1 and Fig. 1a)
Summary
The CCN proteins are a family of intriguing matricellular proteins, playing regulatory roles in various cellular signalling processes and a range of critical biological functions. The modulation of the signal transduction by the CCN proteins can be achieved by association with extracellular matrix components These include sulphated proteoglycans, fibronectin, decorin, low-density lipoprotein (LDL) receptor-related protein (LRP), Notch, and integrins (Chen et al, 2000; Yoshida & Munakata, 2007; Vial et al, 2011; Gao & Brigstock, 2003; Sakamoto et al, 2002; Tan et al, 2009). Despite this wealth of information, the molecular determinants of the interactions of CCN proteins with other molecules are still to be elucidated
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